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Endocrine Care: Tatja Hirvikoski, Anna Nordenström, Torun Lindholm, Frank Lindblad, E. Martin Ritzén, Anna Wedell, and Svetlana Lajic Cognitive Functions in Children at Risk for Congenital Adrenal Hyperplasia Treated Prenatally with Dexamethasone J Clin Endocrinol Metab 2007; 92: 542-548 [Abstract] [Full text] [PDF]

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Re: Adverse Effects Of Prenatal Dexamethasone: The Evidence Is Inconclusive

Svetlana Lajic, Tatja Hirvikoski, Anna Nordenström, Torun Lindholm, Frank Lindblad, Anna Wedell, Martin Ritzén   (7 March 2007)

Adverse Effects Of Prenatal Dexamethasone: The Evidence Is Inconclusive

Heino Meyer-Bahlburg, Maria I. New, MD   (4 January 2007)

Re: Adverse Effects Of Prenatal Dexamethasone: The Evidence Is Inconclusive 7 March 2007
Svetlana Lajic, MD, PhD Karolinska Institutet, Tatja Hirvikoski, Anna Nordenström, Torun Lindholm, Frank Lindblad, Anna Wedell, Martin Ritzén Send letter to journal: Re: Re: Adverse Effects Of Prenatal Dexamethasone: The Evidence Is Inconclusive Svetlana.Lajic{at}ki.se Svetlana Lajic, et al.	We have the following responses to the criticisms by Drs. Meyer-Bahlburg and New of our manuscript, entitled “Cognitive Functions in Children at Risk for Congenital Adrenal Hyperplasia Treated Prenatally with Dexamethasone (JCEM 92, 542-548).” We agree that the ideal study would be a prospective, randomized controlled design, including CAH unaffected and affected individuals, subdivided according to their genotype; long- and short-term treated cases; healthy controls and untreated CAH controls; and controls that have a chronic disease but not involving glucocorticoid treatment. However, a large collaborative study would be needed to ensure such a comprehensive cohort. We encourage large centers with many more treated pregnancies to perform similar studies with direct testing of treated cases. Since our study involved direct testing and interviews with the patients and their parents, it was impossible to blind the assessments. The instruments used had good psychometric properties and could not be influenced by the psychologist. Direct testing and interviews certainly give more valid data than using only a simple questionnaire design. The two sources of controls and the study group did not differ regarding parental socioeconomic status. We also cite other studies of European children showing that there is no difference between urban and rural populations concerning the parameters studied. We have not concluded that the intelligence of the treated children was impaired--the difference did not reach statistical significance. In the group of treated children, there were only four who had been treated until term. This subgroup is obviously too small for separate assessment. We stated that we cannot draw any conclusions regarding this group versus the larger short-term treated group. As stated in our article, long-term prospective studies are necessary to finally conclude whether prenatal dexamethasone treatment has any adverse effects on CNS development. Although such studies are ongoing, very long-term follow up is needed, and it will take many years until results are at hand. Meanwhile, we suggest that those centers that have large cohorts of treated and untreated children with CAH carry out retrospective studies, including neuropsychological testing, similar to ours.
Adverse Effects Of Prenatal Dexamethasone: The Evidence Is Inconclusive 4 January 2007
Heino Meyer-Bahlburg NYS Psychiatric Institute & Columbia University, Maria I. New, MD Send letter to journal: Re: Adverse Effects Of Prenatal Dexamethasone: The Evidence Is Inconclusive meyerb{at}childpsych.columbia.edu Heino Meyer-Bahlburg, et al.	Hirvikoski et al. (1) conclude that their study indicates [adverse] “long-term effects on verbal working memory and on aspects of self-perception” of prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia. While we welcome their follow-up data on cognitive function in this under-researched population, we do not believe that the data justify their conclusions. In the absence of a prospective randomized clinical trial, the best investigative approach to address this issue would be a prospective case-control study involving blinded assessments comparing separately short- and long-term prenatal dexamethasone-treated children to demographically similar untreated children matched for CAH status, taking into account treatment-refusal rates and considering potentially confounding factors unrelated to the patients’ endocrine statuses. The Hirvikoski study, however, did not use blinded assessments, had no CAH-affected controls, and included only three or four children who received long-term treatment. Moreover, their controls came from two different sources and differed from the dexamethasone-treated group in urban-rural background and participation-refusal rates, raising questions regarding sample comparability. In addition, the findings of another recent Scandinavian study (2) on intelligence in CAH children raise the question of whether marginally impaired full-scale IQ in Hirvikoski’s dexamethasone-exposed group reflected effects of CAH itself rather than dexamethasone. Such disease-related effects might account for some of the changes observed in Hirvikoski’s neuropsychological testing. Another problem with Hirvikoski’s observations is that several of the effects, e.g., anxiety, were significant for CAH-unaffected short-term dexamethasone-treated children, but not for the CAH-affected dexamethasone-treated children (although the latter combined the short-term treated CAH boys with the long -term treated CAH girls). This would imply that short-term exposure to dexamethasone during a very early phase of brain differentiation has adverse effects, but long-term exposure does not. This interpretation seems less plausible than that the apparent differences reflect confounding effects from differences between groups in demographic, sex, and/or disease characteristics. It would, therefore, seem premature to make this study the basis for depriving girls with CAH of a prenatal treatment that has very beneficial effects on their genital development, reducing or obviating the need for genital surgery. References 1. Hirvikoski T, Nordenström A, Lindholm T, Lindblad F, Ritzén EM, Wedell A, Lajic S. 2006. Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia affects cognitive functions. J Clin Endocrinol Metab: doi:10.1210/jc.2006-1340 2. Johannsen TH, Ripa CPL, Reinisch JM, Schwartz M, Mortensen EL, Main KM. 2006. Impaired cognitive function in women with congenital adrenal hyperplasia. J Clin Endocrinol Metab 91:1376-1381